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Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

ABSTRACT: OBJECTIVE:The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window. METHODS:This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow. RESULTS:Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation. INTERPRETATION:Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736.

SUBMITTER: Tian DC

PROVIDER: S-EPMC6282815 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

Tian De-Cai DC Shi Kaibin K Zhu Zilong Z Yao Jia J Yang Xiaoxia X Su Lei L Zhang Sheng S Zhang Meixia M Gonzales Rayna J RJ Liu Qiang Q Huang DeRen D Waters Michael F MF Sheth Kevin N KN Ducruet Andrew F AF Fu Ying Y Lou Min M Shi Fu-Dong FD

Annals of neurology 20181102 5

<h4>Objective</h4>The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window.<h4>Methods</h4>This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingol ...[more]

PMID: 30295338

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Project description:Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury.

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Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

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Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

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